human papillomavirus

In December 2015, at the age of 47, I was diagnosed with Stage IV oral squamous cell carcinoma.

More simply, I have advanced cancer of the head and neck. While initial treatment with grueling chemo-radiation appeared successful, the cancer returned one year later in both of my lungs. My prognosis shifted from potentially curable to terminal disease. The news was shocking and devastating—not just for me, but for my wife, two teenage daughters, and the rest of our family and friends.

Suddenly, my life revolved around regular appointments for chemotherapy, radiation therapy, imaging procedures, and frequent checkups. I made seemingly endless, unscheduled hospital emergency room visits—including one trip to the intensive care unit—to address some of the more severe toxicities from treatment.

All told, I suffered from more than a dozen side effects related to treatment and/or cancer progression. Some are temporary; others permanent. These include anxiety, depression, distorted sense of taste, clots forming in my blood vessels, dry mouth, weight loss, and many more.

My cancer started with a human papillomavirus (HPV) infection, a virus that is preventable with vaccines available for adolescent girls since 2006 and boys starting in 2011. The Food and Drug Administration (FDA) has approved three vaccines to prevent HPV infection: Gardasil®, Gardasil® 9, and Cervarix®. These vaccines provide strong protection against new HPV infections for young women through age 26, and young men through age 21, but they are not effective at treating established HPV infections. It was too late for me in 2011 when the HPV vaccine was made available to young men, and I was 43 years old.

According to the Centers for Disease Control and Prevention (CDC), more than 30,000 new cancers attributable to HPV are diagnosed each year. Unlike human immunodeficiency virus (HIV), which is spread by blood and semen, HPV is spread in the fluids of the mucosal membranes that line the mouth, throat, and genital tracts, and can be passed from one person to another simply via skin-to-skin contact.

While most HPV cases clear up on their own, infection with certain high-risk strains of HPV can cause changes in the body that lead to six different types of cancer, including cancers of the penis, cervix, vulva, vagina, anus, and head and neck (the last of which is what I have). Two of these, HPV strains 16 and 18, are responsible for most HPV-caused cancers.

Researchers believe that it can take between 10 and 30 years from the time of an initial HPV infection until a tumor forms. That’s why preventing HPV in the first place is so important and the HPV vaccine is so essential.

However, only 49.5 percent of girls and 37.5 percent of boys in the United States were up to date with this potentially lifesaving vaccination series, according to a 2017 CDC report. In sharp contrast, around 80 percent of adolescents receive two other recommended vaccines—a vaccine to prevent meningococcus (PDF), which causes bloodstream infections and meningitis, and the Tdap vaccine to prevent tetanus, diphtheria, and pertussis.

Even if you don’t think your child is at risk for HPV now, they almost certainly will be. HPV is extremely common. Nearly everyone gets it at some point; in fact, the CDC estimates that more than 90 percent and 80 percent of sexually active men and women, respectively, will be infected with at least one strain of HPV at some point in their lives. Around one-half of these infections are with a high-risk HPV strain.

As a cancer patient with a terminal prognosis, I find it infuriating that the HPV vaccine is tragically underutilized more than a decade since its introduction. Two simple shots administered in early adolescence can reduce a child’s risk of receiving a cancer diagnosis much later in life.

Parents who oppose the use of vaccines cite popular misconceptions that they are unsafe, ineffective, and that immunity is short-lived. Others argue that receiving the HPV vaccine may increase sexual promiscuity. Films like Vaxxed based on research that has been discredited, and directed by a researcher who fled the United Kingdom due to the misleading uproar he created, are still quoted as science.

Regardless, the fact remains that millions of adolescents aren’t getting a vaccine to prevent a virus known to cause cancer. We must counter untrue, exposed, and discredited research that keeps some parents from having their children vaccinated and put an end to the campaign of misinformation.

Viruses that are preventable, such as HPV, should be eradicated just like previous success with polio and smallpox. Cancers that are preventable through HPV vaccination should be prevented. The safety and efficacy of these vaccines are no longer subject to serious debate (PDF). Research has shown that vaccinations work; they keep children healthy, save lives, and protect future generations of Americans—but only when they are utilized.

The lesson: Don’t wait. Talk to your pediatrician about vaccinating your 11-year-old boys and girls against HPV today to eradicate this cancer-causing virus.

I only wish my parents had that opportunity when I was young, as it could have prevented the cancer that’s killing me.

In an era of $500,000 cancer treatments, you’d expect a vaccine series that costs about $300 and helps prevent several types of cancer to be popular with physicians, insurers, and consumers. It’s not, and, as a result, people are dying. I should know — I’m one of them.

The human papillomavirus (HPV) can cause changes in the body that lead to six cancers: cervical, vaginal, and vulvar cancer in women; penile cancer in men; and anal cancer in both women and men. It can also cause oropharyngeal cancer — cancer in the back of the throat, including the base of the tongue and tonsils — in both sexes. In the U.S., approximately 30,000 new cancers attributable to HPV are diagnosed each year.

In 2006, the first vaccine became available to protect against HPV infection. I was 38 years old at the time, well above the upper age limit of 26 the Centers for Disease Control and Prevention recommends for getting the vaccine. Ideally it should be given before the teen years, but can be given up to age 26.

Uptake of the HPV vaccine in the U.S. is abysmal, with just 49 percent of girls and 37 percent of boys having received the recommended HPV vaccination series.

Individuals who oppose the use of vaccines argue that safety concerns should preclude the use of the HPV vaccine. I disagree. The safety and effectiveness of this vaccine to protect against cancer-causing strains of the HPV virus have been unquestionably proven. Others point to side effects of the HPV vaccine as a reason not to vaccinate young Americans. These may include pain, swelling, redness, itching, bruising, bleeding, or a lump at the injection site as well as headache, fever, nausea, dizziness, tiredness, diarrhea, abdominal pain, and sore throat. Most people who get the vaccine experience no side effects from it other than the pain that accompanies most shots.

Missing from the discussion are the risks of not getting the vaccine. As someone with HPV-related oropharyngeal cancer, I can describe a few of them. And I can say with certainty I would gladly have experienced any of the vaccine-related side effects rather than the dozen or so “side effects” of the cancer and its treatment that I’m living with. I’ve illustrated them on the image below.

Some of these side effects, like hair loss, aren’t hazardous. Others are. I’ve spent time in an intensive care unit for my rapid heart rate, and have had to go to the emergency department several times for my pleural effusion and other issues. All of these pale beside the biggest “side effect” — a terminal disease that will eventually take my life.

I urge all parents to talk to your child’s doctor about the HPV vaccine. I wish my parents had that opportunity when I was young, as it could have prevented the cancer that’s killing me.

Incidence of human papillomavirus (HPV)-related oropharyngeal cancer is increasing. There is interest in identifying healthy individuals most at risk for development of oropharyngeal cancer to inform screening strategies.

Patients and methods

All data are from 2009 to 2014, including 13 089 people ages 20–69 in the National Health and Nutrition Examination Survey (NHANES), oropharyngeal cancer cases from the Surveillance, Epidemiology, and End Results (SEER 18) registries (representing ∼28% of the US population), and oropharyngeal cancer mortality from National Center for Health Statistics (NCHS). Primary study outcomes are (i) prevalence of oncogenic HPV DNA in an oral rinse and gargle sample, and (ii) incident oropharyngeal squamous cell cancer.

Results

Oncogenic oral HPV DNA is detected in 3.5% of all adults age 20–69 years; however, the lifetime risk of oropharyngeal cancer is low (37 per 10 000). Among men 50–59 years old, 8.1% have an oncogenic oral HPV infection, 2.1% have an oral HPV16 infection, yet only 0.7% will ‘ever’ develop oropharyngeal cancer in their lifetime. Oncogenic oral HPV prevalence was higher in men than women, and increased with number of lifetime oral sexual partners and tobacco use. Men who currently smoked and had ≥5 lifetime oral sexual partners had ‘elevated risk’ (prevalence = 14.9%). Men with only one of these risk factors (i.e. either smoked and had 2–4 partners or did not smoke and had ≥5 partners) had ‘medium risk’ (7.3%). Regardless of what other risk factors participants had, oncogenic oral HPV prevalence was ‘low’ among those with only ≤1 lifetime oral sexual partner (women = 0.7% and men = 1.7%).

Conclusions

Screening based upon oncogenic oral HPV detection would be challenging. Most groups have low oncogenic oral HPV prevalence. In addition to the large numbers of individuals who would need to be screened to identify prevalent oncogenic oral HPV, the lifetime risk of developing oropharyngeal caner among those with infection remains low.

Introduction

Human papillomavirus (HPV) is the most commonly sexually transmitted infection in the United States. HPV now causes ∼70% of all oropharyngeal squamous cell cancer (OPC) in the United States [1] and the incidence of HPV-related OPC (HPV-OPC) among men has more than doubled over the past 20 years [2]. Indeed, OPC is projected to be more common than cervical cancer in the United States by 2020 [3]. Given the ‘epidemic’ of HPV-OPC, there is interest in identifying specific groups that could benefit from screening, if effective tests were developed.

Sexual behaviors responsible for exposure to oral HPV infection are common (80% of the US population reports ever performing oral sex) [4]. Given the ubiquitous exposure to HPV infection and resulting anxiety [5], there is interest in identifying healthy individuals most at risk for development of OPC. As oncogenic oral HPV infection is the precursor to malignancy, identification of individuals with oncogenic oral HPV infection may point to individuals with premalignant disease. Such risk triage could both inform screening approaches and assist the public in understanding personal risk. This analysis therefore aims to understand how common HPV16, oncogenic HPV and HPV-OPC are in groups of people with different risk factor profiles.

Methods

Study population

This study included 13 089 people ages 20–69 years old who participated in National Health and Nutrition Examination Survey (NHANES) between 2009 and 2014 and had oral HPV DNA testing. Analyses involving number of oral sex partners were limited to ages 20–59, with data for number of oral sex partners, resulting in a sample size of 9425. Incidence and incidence-based mortality data from SEER 18 registries between 2009 and 2014 [6] were used with NCHS mortality data for projections of OPC risk.

HPV measurement

As previously described [7, 8] oral HPV DNA was tested in exfoliated cells collected from an oral rinse and gargle sample using PCR amplification using PGMY 09/11 consensus primers and line blot for the detection of 37 specific HPV types. Oncogenic oral HPV was defined as detection of any of the following 12 types: HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 [9].

To better understand subgroup risk, prevalence of oncogenic HPV and HPV16 were explored stratifying by multiple factors including sex, sexual behavior, age, and current smoking. Groups with similar prevalence were combined to create parsimonious risk stratification of people with similar prevalence.

Results

Oncogenic oral HPV and oral HPV16 infection are rare in the general US population. As expected, prevalence of infection is higher among men than women of every age group (oncogenic HPV; 6.0% versus 1.1%, P < 0.001; Table 1). Prevalence of oncogenic oral HPV is contrasted with risk of OPC in Table 1 by sex and age groups. While oncogenic oral HPV is detected in 3.5% of all adults age 20–69, the lifetime risk of OPC is low (37 per 10 000). For example, among men 50–59 years old, 8.1% have an oncogenic oral HPV infection, 2.1% have an oral HPV16 infection, yet 0.7% will ‘ever’ develop OPC in their lifetime; and risk of developing OPC in the next 10 (0.2%) or 20 (0.4%) years is even lower (Table 1).

Table 1.

Oral HPV prevalence by sex and age, compared with the risk of developing oropharyngeal cancer (OPC) in each group

Risk spectrum: infection to cancer

NHANESa (prevalence)

SEERb (OPC risk: cases/100 people)

Sex

Age

Oncogenic Oral HPV (%)

Oral HPV16 (%)

Lifetime (%)

Next 20 years (%)

Next 10 years (%)

Men

20–29

4.8

1.1

0.7

0.01

<0.01

30–39

4.7

1.5

0.7

0.07

0.01

40–49

6.2

2.3

0.7

0.3

0.06

50–59

8.1

2.1

0.7

0.4

0.2

60–69

6.1

2.4

0.5

0.4

0.3

Total

6.0

1.9

0.7

–

–

Women

20–29

1.4

0.3

0.2

<0.01

<0.01

30–39

1.0

0.3

0.2

0.01

<0.01

40–49

0.8

0.1

0.2

0.05

0.01

50–59

1.6

0.5

0.2

0.08

0.03

60–69

0.7

0.1

0.1

0.10

0.05

Total

1.1

0.3

0.2

–

–

Men and women

All

3.5

1.1

0.4

a- Weighted prevalence accounting for NHANES study design weights to reflect the general US population.

b- Estimates of OPC risk combine data on cancer occurrence from SEER with population data. OPC is shown as risk per 100 people to contrast with HPV prevalence. For reference in interpretation, 0.6% risk represent that 0.6 people out of the 100 (or 6 out of 1000, or 600 out of 100 000) would develop OPC.

While prevalence of oncogenic oral HPV infection is low, the distribution of infections is not representative of the population (supplementary Table S1, available at Annals of Oncologyonline). Indeed 84% of oncogenic oral HPV infections in 20- to 69-year olds were among men. To elucidate why oncogenic oral HPV was more concentrated among certain groups, behavioral characteristics were considered. Performing oral sex and smoking are each strongly associated with detection of oncogenic oral HPV (Table 2) and HPV16 (supplementary Table S2, available at Annals of Oncology online). Oncogenic oral HPV prevalence is low (<2.5%) among both men and women who never performed oral sex. Prevalence of oncogenic oral HPV increased with number of lifetime oral sexual partners, up to 14.4% in men age 20–59 years old with ≥10 lifetime oral sexual partners (Table 2).

b-Wald F test (based on transforming the Wald χ2) for independence of row variable and oral HPV16, not accounting for sex (except where sex is the row variable).

C- Data on number of lifetime oral sex partners was not collected consistently in those 60 and older so is only presented among those 20–59 years old.

Oncogenic oral HPV prevalence was explored by sex, sexual behavior, and tobacco use to better understand groups that have higher and lower prevalence (Figure 1). Regardless of what other risk factors participants had, oncogenic oral HPV prevalence was low among those with only ≤1 lifetime oral sexual partner (women = 0.7% and men = 1.7%). Oncogenic oral HPV prevalence doubled among women with ≥2 versus 0–1 lifetime oral sexual partners (1.5% versus 0.7%, P = 0.02), but remained low among women with higher number lifetime oral sexual partners (Table 2). Oncogenic oral HPV prevalence was highest among men who currently smoked and had ≥5 lifetime oral sexual partners (14.9%, 95% CI = 11.4–19.1). Men with only one of these risk factors (i.e. either smoked and had two to four partners or did not smoke and had ≥5 partners) had ‘medium risk’, with 7.3% (95% CI = 5.8–9.1) oncogenic oral HPV prevalence (Figure 1). Findings were similar when considering oral HPV16 infection specifically.

What is my risk of oral HPV? Prevalence of oral HPV16 and any oncogenic oral HPV infection by risk group. In the ‘very low-risk’ group (among women with 0–1 lifetime oral sexual partners), oncogenic oral HPV was similar among smokers and nonsmokers (1.8% versus 0.5%, P = 0.26). In the ‘low-risk’ group of women, oncogenic oral HPV prevalence was 1.5% among women with two or more lifetime oral sexual partners. In the ‘low-risk’ group of men, oncogenic oral HPV prevalence was 1.7% among men with 0–1 lifetime oral sexual partners and was higher among men who did not smoke and had 2–4 lifetime oral sexual partners (4.1%, P = 0.0042). In the ‘medium risk’ group, oral HPV16 prevalence was 7.1% among men who smoke and had 2–4 partners and 7.4% among men who do not smoke and had 5+ partners (P = 0.87).

Discussion

This analysis highlights that the yield of oncologic oral HPV screening would be limited in most groups in the United States. With the increasing incidence of OPC, there is a need to understand how to identify individuals at risk of OPC. Oncogenic oral HPV detection is attractive as it samples the relevant epithelium in a non-invasive method, has relatively low cost and serves as a biomarker for HPV-OPC. However, for screening to succeed, a high prevalence population is needed to limit false positives, and balance the psychologic and physical harms of screening with the benefits.

From this analysis, it is clear that screening based upon oncogenic oral HPV detection would be challenging. Women across all categories have low prevalence of infection and low risk of OPC and therefore benefits of screening are unlikely to outweigh harms in this group. The higher prevalence of oncogenic oral HPV in men than women is thought be due to both a higher per partner risk of acquisition when performing oral sex [11, 12], and decreased clearance among men than women [11, 13]. While there are specific risk groups of men enriched for oncogenic oral HPV, most men have low prevalence of infection. Even among the elevated risk group, the majority of men do not have a prevalent oncogenic oral HPV. In addition to the large numbers of individuals who would need to be screened to identify prevalent oncogenic oral HPV, the lifetime risk of developing OPC among those with infection remains low [11, 14].

These characteristics suggest that other tests will need to be combined or supplant present methods to accurately identify those with the greatest risk of OPC in the population. Serum HPV oncoprotein antibody tests are specific [15], but are even rarer than oral HPV16 infection [16], so may be impractical to use in most groups. An additional challenge for screening is that precursor lesions for HPV-OPC have not been found and the ability to detect lesions early in an ‘elevated-risk’ group is unknown.

With growing appreciation of the relationship between oral sex, infection, and cancer, some individuals have questions about their risk of having oncogenic oral HPV infection. To address concerns about infection among individuals with high number of oral sex partners or others concerned about their cancer risk, the infographic can be used to reassure that oncogenic oral HPV prevalence is low among most groups. This analysis has several imitations. Data on oral HPV infection were cross-sectional, with no information linking HPV and SEER data used for cancer risk. Comparing oncogenic oral HPV prevalence and OPC risk in this way informs potential future screening studies, and personal risk assessment. In summary, this analysis shows that screening based upon oncogenic oral HPV infection will not be useful and presents data to communicate to the layperson the low risk of infection and cancer.

Acknowledgements

The authors acknowledge Maura Gillison who led the testing for oral HPV in NHANES provided in the publicly available dataset. This dataset has provided investigators the opportunity to better understand the epidemiology of oral HPV infection in the United States. We also acknowledge the contributions of the Oral Cancer Foundation.

Funding

National Institute of Dental and Craniofacial Research (NIDCR) (R35 DE026631).

About half of American teenagers have been vaccinated against the human papillomavirus (HPV), the most common sexually transmitted infection in the United States. Should adult women follow suit?

Yes, says Lauri Markowitz, a Centers for Disease Control and Prevention medical epidemiologist who has worked with the advisory committee that makes national vaccination recommendations. “Women 18 to 26 should be vaccinated.”

There’s good reason to follow that recommendation. According to the American Cancer Society, about 12,820 new cases of cervical cancer will be diagnosed in U.S. women this year and more than 4,000 will die of the disease. HPV is thought to be responsible for more than 90 percent of all cervical and anal cancers in men and women. The virus also causes vaginal, vulvar and throat cancers and genital warts.

Although the majority of HPV infections do not cause cancer — most people with an infection never show any symptoms, and infections usually go away on their own — some strains are particularly dangerous. Gardasil 9, the newest HPV vaccine approved by the Food and Drug Administration, protects against nine such strains and, researchers say, may be able to prevent up to 90 percent of cervical cancers. (Older vaccines protect against fewer strains of HPV.)

However, confusion about the way HPV vaccines protect against infection can deter some women. Gardasil 9 is approved for women up to age 26. Like other vaccines, it spurs the body’s immune system to defend itself against a virus. The FDA and CDC say the HPV vaccines are safe and extremely effective: HPV rates in women ages 14 to 19 years fell 64 percent within six years of the vaccine’s introduction in the United States in the mid-2000s and 34 percent in women ages 20 to 24.

The vaccines are most effective if administered before a woman becomes sexually active. The longer a woman has been sexually active and the more partners she has had, the more opportunities she has had to become infected with an HPV strain that overlaps with the vaccine. If she is vaccinated at an older age, the vaccine may be less effective in lowering her cancer risk, Markowitz says. The vaccine can’t clear any HPV that has taken hold; it can only prevent future infection. So essentially if you already have been exposed to one of the strains it protects against, it will be useless against that strain.

That doesn’t mean it’s useless to get vaccinated if you’re older than the recommended age of 11 or 12, Markowitz says. “Your chances of being protected are decreasing, but you will still have some protection,” she says. Although the likelihood that a sexually active woman has been infected with one of the strains the vaccine protects against increases as a woman has more partners, those who didn’t receive the vaccine at the recommended age are still urged to get vaccinated to increase the odds of protection.

Some insurance does not cover the vaccine for those older than 18 — the shots can be costly, though the manufacturer may provide assistance — but it really varies across the board.

Surgeons at the University of Pennsylvania have achieved a global first with the use of a fluorescent dye that identifies cancerous cells in lymph nodes during head and neck cancer procedures.

The study, led by otorhinolaryngologist Jason G. Newman, seeks to test the effectiveness of intraoperative molecular imaging (IMI), a technique that illuminates tumors to provide real-time surgical guidance.

More than 65,000 Americans will be diagnosed with head and neck cancers in 2017, accounting for approximately 4 percent of all cancers in the United States, according to the National Cancer Institute. About 75 percent of these cancers are caused by tobacco and alcohol use, followed by human papillomavirus (HPV) as a growing source for their development.

Common areas affected by these cancers include the mouth, throat, voice box, sinuses and salivary glands, with typical treatments including a combination of surgery, radiation and chemotherapy.

Lymph nodes, which act as filters for the immune system, are often among the first organs affected by head and neck cancers as they spread or resurface. Initial surgeries may leave microscopic cancerous cells undetected in the lymphoid tissue, heightening the risk that a patient’s condition will return after the procedure.

“By using a dye that makes cancerous cells glow, we get real-time information about which lymph nodes are potentially dangerous and which ones we can leave alone,” Newman said. “That not only helps us remove more cancer from our patients during surgery, it also improves our ability to spare healthy tissue.”

With the aid of a fluorescent dye, surgeons are able to key in on suspicious tissue without removing or damaging otherwise healthy areas. Previously adopted for other disease sites in the lungs and brain, the practice now allows Newman’s team to experiment with indocyanine green (ICG), an FDA-approved contrast agent that responds to blood flow.

Newman explained that since tumor cells retain the dye longer than most other tissues, administering the dye prior to surgery singles out the areas where cancer cells are present.

The current trial at Penn will enable researchers to determine whether ICG is the most suitable dye for head and neck cancers and provide oncologists with a deeper understanding of how cancer spreads in the lymph nodes.

Source: www.newswise.com
Author: University of North Carolina Health Care System

A blood test for the human papillomavirus, or HPV, may help researchers forecast whether patients with throat cancer linked to the sexually transmitted virus will respond to treatment, according to preliminary findings from the University of North Carolina Lineberger Comprehensive Cancer Center.

HPV can cause oropharyngeal cancer, which is a cancer of the throat behind the mouth, including the base of the tongue and tonsils. Studies have shown that patients with HPV-positive oropharyngeal cancer have better outcomes than patients whose cancer is not linked to the virus.

Preliminary findings presented at this year’s American Society for Radiation Oncology Annual Meeting suggest a genetic test for HPV16 in the blood could be useful to help assess risk for patients, and could help identify patients suitable for lower treatment doses.

“Our work on this blood test is ongoing, but we are optimistic that ‘liquid biopsy’ tests such as ours may be useful in the personalization of therapy for many patients with HPV-associated oropharyngeal cancer,” said the study’s senior author Gaorav P. Gupta, MD, PhD, UNC Lineberger member and assistant professor in the UNC School of Medicine Department of Radiation Oncology.

To avoid over-treating patients and to spare them from toxic treatment side effects, UNC Lineberger’s Bhisham Chera, MD, an associate professor in the radiation oncology department, led studies testing whether favorable-risk patients with HPV-positive oropharyngeal cancer can be treated successfully with lower doses of radiation and chemotherapy. A phase II clinical trial using this de-intensified regimen have shown “excellent” cancer control, Chera said.

The researchers used a number of selection criteria to identify patients who can benefit from lower-doses: patients had to be positive for HPV, and they had to have smoked fewer than 10 pack years. Chera said this system is not perfect, however. The researchers have seen cancer recur in non-smoking patients as well as “excellent” cancer control in longtime smokers.

“This has led us to question whether we can get better prognostication with other biomarkers,” Chera said.

They developed a test that can detect HPV16 circulating in the blood, and found that circulating HPV16 DNA was detectable using the test in the majority of a group of 47 favorable-risk oropharyngeal cancer patients.

In a finding that seems counterintuitive, they discovered that very low or undetectable HPV16 pretreatment levels in their blood actually had higher risk of persistent or recurrent disease for chemotherapy and radiation treatment. In contrast, patients with high pretreatment levels of HPV16 in their blood had 100 percent disease control.

They hypothesized that, potentially, the patients with undetectable/low pre-treatment HPV16 levels in the blood may have different, more radiation/chemotherapy resistant cancers.

“Our current theory is that these patients with low or undetectable levels of HPV16 have a different genetic makeup—one that is perhaps less driven purely by HPV, and thus potentially less sensitive to chemotherapy and radiation,” Gupta said. “We are performing next generation sequencing on these patients to search for additional genetic markers that may give us a clue regarding why they have a worse prognosis.”

They also identified a subset of patients who rapidly cleared the HPV16 from their blood. Researchers hypothesize that they could use their findings to further stratify patients who may be eligible for lower intensity treatment.

“A tantalizing – and yet currently untested – hypothesis is whether this subset of ultra-low risk patients may be treated with even lower doses of chemoradiotherapy,” Gupta said.

New research from Georgetown University in Washington, D.C., investigates how the human papillomavirus promotes cancer. The findings might point to a potential new and improved strategy for targeted treatment.
The human papillomavirus (HPV) refers to a group of viruses transmitted through sexual contact. Some types of HPV cause various kinds of cancer, including mouth, anus, and cervical cancer.

According to data from the Centres for Disease Control and Prevention (CDC), around 1 in 4 people in the United States are infected with HPV.

Although treatments for HPV-related conditions do exist, they either target non-cancerous outcomes (such as genital warts) or they focus on the prevention of cancer through screening of abnormal cell activity.

Treatments for cancers caused by HPV include surgical interventions and chemotherapy, but at present, none of the options specifically address the viral source.

Researchers from Georgetown University Medical Center in Washington, D.C., have now identified the mechanism that promotes the survival of cancerous cells due to HPV. The study, which was led by Dr. Xuefeng Liu, describes a molecular apparatus that renders cancer cells “immortal.” Understanding how this apparatus works may lead to better targeted treatments in the future, the researcher suggests.

“There is no targeted treatment now for these cancers since German virologist Harald zur Hausen, Ph.D., discovered in 1983 that HPV can cause cervical cancer,” says Dr. Liu.

“Recently,” he adds, “the numbers of HPV-linked head and neck cancers have increased in the U.S. Now we have a chance to develop and test a very specific, potentially less toxic way to stop these cancers.”

Imagine a vaccine that protects against more than a half-dozen types of cancer—and has a decade of data and experience behind it.

We have one. It’s the human papillomavirus (HPV) vaccine, and it was approved for the U.S. market back in June 2006. It can prevent almost all cervical cancers and protect against cancers of the mouth, throat and anus. It also combats the sexually transmitted genital warts that some forms of the virus can cause.

On Wednesday, two researchers who completed fundamental work on these vaccines received one of this year’s prestigious Lasker Awards, a group of medical prizes sometimes called the “American Nobels.” Douglas Lowy and John Schiller, whose research provided the basis for the HPV vaccine, were selected alongside a researcher who separately unraveled key aspects of metabolic control of cell growth. Planned Parenthood was also given an award, for its public service. Lowy and Schiller, who both work at the U.S. National Cancer Institute (NCI), received the Lasker for their research on animal and human papillomaviruses—work that enabled the development of a vaccine against HPV-16 type, a form of the virus that fuels many HPV malignancies. The duo’s experiments proved that the vaccine is effective in animals, and they also conducted the first clinical trial of an HPV-16 vaccine in humans. That gave pharmaceutical companies the evidence they needed to invest in their own vaccines designed to protect against multiple kinds of HPV, and ultimately led to the versions administered around the world today.

Yet HPV shots have had a difficult run. Despite overwhelming evidence of their safety and effectiveness, in some developed countries—including the U.S.—HPV inoculations face opposition from individuals and groups that fear the shots are still too new and unproved to use on their children. The HPV vaccine also faces another hurdle beyond other routine pediatric shots: the virus is transmitted via sexual contact—which some parents and communities believe teens should not or will not have, and thus that the shots should not be mandatory. (The U.S. Centers for Disease Control and Prevention [CDC] currently recommends administering two doses of the vaccines to children 11 to 12 years old, administered at least six months apart.)

Scientific American spoke with Schiller, a virologist, about his and Lowy’s award-winning HPV research, their future plans and how to combat anti-vaccine attitudes.

[An edited transcript of the interview follows.]

What’s the biggest hurdle to getting more coverage with the HPV vaccine?
The biggest problem is actually not in the West or most developed countries; it is in the lower- and middle-income countries because of availability there and vaccine prices that limit availability. In those settings vaccine acceptance is actually very high. But those settings present the biggest problem, since some 85 percent of cervical cancers occur in low-resource settings. In the more developed countries there are many different factors involved [in vaccine hesitancy], and they differ by country. In the U.S. it is more about fear of vaccines in general. And there are some issues with HPV vaccines specifically related to this being about a sexually transmitted disease.

So far, more than 270 million doses of HPV vaccines have been distributed worldwide. But in the United States, by 2015 only 28 percent of teen males and 42 percent of teen girls had received the full course of three shots then recommended by the CDC. How can the science community help combat HPV vaccine hesitancy?
There are quite a few studies that show one of the biggest issues is that the vaccine is not being promoted sufficiently by pediatricians and general practitioners. If you look at other vaccines like for meningitis and hepatitis B—which are also administered to adolescents and could be given in the same visit as HPV—they are given at greater rates than HPV. So, there is some disconnect in communication between pediatricians and parents there. Part of the problem here is that the HPV vaccine is a prophylactic vaccine to prevent a disease—cervical cancer—that those providers never see. Obstetrician-gynecologists see it, but pediatricians don’t, which is the opposite of most other childhood or pediatric vaccines. Right now it’s being singled out as something special instead of treated as a routine childhood or adolescent vaccine. But we’ve had this vaccine for 10 years now and it’s not the new kid on the block anymore.

Mounting evidence suggests that among people who feel vaccines are unsafe, any new data showing that they arereally safe does not move the needle to convince them. So, what can be done?
My feeling is that there is a certain percentage of people who, no matter what facts you present to them, they are just not going to be convinced. Quite frankly it doesn’t pay to spend a lot of resources trying to convince that relatively small fraction. What we need to focus on is a much larger fraction of the population who aren’t having their kids vaccinated for reasons like convenience—like it’s a hassle—or they just need a bit more information to make them comfortable. People against all vaccines, those people would not be convinced to get an HPV vaccine so it’s not worth spending a lot of resources on them. I think one of the things that would increase HPV vaccine coverage would be allowing people to get them at their local CVS. I’m not an expert on this, but I have a daughter who as a teen spent much more time at the local CVS than at her local Kaiser clinic. Different states have different laws about which vaccines can and can’t be delivered at pharmacies—but if someone could go get an HPV vaccine at the same place they get their flu vaccine, presumably it would lead to an uptick.

I see you studied molecular biology as an undergrad at the University of Wisconsin–Madison. Did you always want to work on vaccines?
No, absolutely not. When I first started out I was an academic purist and thought you should study knowledge for its own sake. I was fascinated by molecular biology. When I first heard about the way metabolism works in bacteria, plants and humans, that just wowed me because that was a common feature of all life. I just wanted to study that. I thought people who did translational work were sort of selling out to the man—this was in the 1970s. I didn’t get interested in vaccines until much later. Now, I’m very fascinated with translational research.

So, what changed?
It was a very gradual thing. To this day we still do basic research, and it’s still intrinsically valuable to do basic research because you don’t know when it will lead to a transformational breakthrough.

What led you to work on HPV?
When I had just joined the field, suddenly there was this discovery that made papilloma viruses important for human health as opposed to just an understanding of how cells become cancerous. I had joined Doug Lowy’s lab at the National Cancer Institute as a postdoc back in 1983, and the second lecture I went to there was by Harald zur Hausen—who later won the Nobel Prize—and his lecture was saying “eureka! We found a virus that seems to cause 50 percent of cervical cancers”—and that virus turned out to be a human papilloma virus strain, HPV-16. So basically we went from looking at a model about how a normal cell transforms to become carcinogenic to something probably involved in causing human cancer. It was somewhat serendipitous.

What are you working on now?
One thing we are doing at the NCI, and cosponsored by the Bill & Melinda Gates Foundation, is testing if one dose of HPV vaccine is enough to provide long-term protection. It would be transformative, especially in the developing country setting, if you could just have one dose at a younger age. This new trial is going to be done in Costa Rica in collaboration with the Costa Rican government. That’s the site where we had done a prior pilot trial that suggested one dose may be enough.

We are also looking into cancer immunotherapy work. It turns out that these virus-like particles that we work with for the HPV vaccine—these are typically the outer shell of a virus, like from the HPV-16 strain or other animal, or human papilloma virus particles—have a unique ability to infect tumor cells and bind to them specifically. So we are using that knowledge to develop cancer therapies that are broad-spectrum. It turns out these cancers, like melanoma, do bind these particles, specifically.

One other thing we are doing is trying to develop vaccines that would treat herpes simplex infections and HPV infections in the female genital tract. Again, this would take advantage of these virus-like particles’ structures.

Last year I interviewed Michael Sofia, who won a Lasker Award for his hepatitis C vaccine work. The name of that vaccine, sofosbuvir—brand name Sovaldi—is a nod to his last name. But the National Institutes of Health (NIH) do a lot of early-stage research, and then it’s passed off to private companies that develop it further. Your name isn’t part of the HPV vaccines Gardasil or Cervarix, for example. Is it frustrating doing a lot of that behind-the-scenes work?
It’s funny because I would never have thought of that. It would have never entered my mind to name a vaccine after ourselves. We are so used to doing this translational work. My job is to move a project along so it’s interesting enough for a company to invest hundreds of millions of dollars for the benefit of large numbers of people. NIH doesn’t have the money to do phase III trials for lots of drugs, and even if they did it wouldn’t lead to all the drugs we need—because NIH wouldn’t have the money to develop them. This translational and basic research is what NIH does best. That work is way too fraught with failure for companies to do it all. It has to be done in the public sector, and then when things look more promising companies can take it over.
What advice would you offer someone considering becoming a scientist now?
It’s got to be a passion because being a scientist—especially early in your career—is more a lifestyle than occupation. You have to really want to do it, because there is a lot of uncertainty—especially about running your own lab and getting funding. Success and failure can be on a knife’s edge sometimes. The other thing is that you need to be strategic about thinking of what you want to go into, and that’s hard for young people because they don’t have the perspective: There are some fields just opening up ripe for discoveries. And there are some areas that are very mature, that we have been working on for a long time, where there are a lot of scientists working already—so the chances of making a big impact are lower. From my own life, this is like when we started with human papilloma viruses. When I went into this field, we had just been given the tools to study them and so it seemed like a great opportunity to get involved. In some ways it’s best if you can pick an emerging field with new tools to answer big questions. But you have to pick something you are really interested in and go with it.

The other thing I’d say is read a lot. Now with PubMed and access to all these journals there is no excuse for not knowing the background in something that basically has already been done. Young people tend to want to get out and do experiments, but a few days searching PubMed may save someone years of work trying to reinvent the wheel.

Right now, what would you say is the biggest challenge—or one of the biggest challenges—that needs to be solved?
That’s a really tough one. I think as scientists we are all sort of locked into the things we study. I could say cancer, obviously. But Alzheimer’s is something we obviously need to solve. HIV infection. All these different things. One of the things that really needs to be solved in terms of the whole scientific enterprise now is stable funding. Right now we are in a situation where there are too many good scientists—especially young scientists—competing for a limited pot of money. So you lose some good people because there’s not enough money to go around. Also, people are forced to do relatively mundane things that are really a methodological extension of something they’ve done before instead of something truly transformative that would have a large chance of failure. Grant reviewers are looking at something likely to succeed and move the field incrementally, or something transformative that may have a high chance of failure, and have to make those decisions. This is an issue across the sciences. The obvious solution would be to have more funding, but then that raises the question about how to do that. And I’m not a politician.

What, if anything, does this Lasker Award do for your work?
Quite honestly, probably nothing, because one of the nice things about being part of intramural research [at NIH] is that I have stable funding. I’ve had six people in my lab for the last 25 years, so this won’t lead to more grants or me doubling the size of my lab, or anything like that. I’m happy with my moderate-sized lab and collaborations with a lot of great people. That’s why I’m here. Every four years we have a site visit, which is a retrospective review of “what have you done for us lately,” and if it’s reasonable I will continue to get funding. So the award won’t affect my research career much at all.

Right now, some in the scientific community fear amid this political climate that facts matter less than they once did and thus science matters less. What’s your take on that?
Obviously, my perspective is science matters a lot. I really can’t comment on what’s happening in the country overall—and whether this is something that is pervasive where science is really held in less esteem, or it’s that there is a vocal minority being heard a lot now. I would hope it’s the latter.

The proportion of oral cancers caused by the human papillomavirus has risen significantly in Canada, say researchers, who suggest the infection is now behind an estimated three-quarters of all such malignancies. In a cross-Canada study, published Monday in the Canadian Medical Association Journal, the researchers found the incidence of HPV-related oropharyngeal cancers increased by about 50 per cent between 2000 and 2012.

“It’s a snapshot of looking at the disease burden and the time trend to see how the speed of the increase of this disease (is changing),” said co-author Sophie Huang, a research radiation therapist at Princess Margaret Cancer Centre in Toronto.

Researchers looked at data from specialized cancer centres in British Columbia, Alberta, Ontario and Nova Scotia to determine rates of HPV-related tumours among 3,643 patients aged 18 years or older who had been diagnosed with squamous cell oropharyngeal cancer between 2000 and 2012.

HPV is the most common sexually transmitted infection worldwide. Most people never develop symptoms and the infection resolves on its own within about two years.

“In 2000, the proportion of throat cancer caused by HPV was estimated at 47 per cent,” said Huang. “But in 2012, the proportion became 74 per cent … about a 50 per cent increase.”

Statistics from a Canadian Cancer Society report last fall showed 1,335 Canadians were diagnosed in 2012 with HPV-related oropharyngeal cancer and 372 died from the disease.

HPV is the most common sexually transmitted infection worldwide. Most people never develop symptoms and the infection resolves on its own within about two years. But in some people, the infection can persist, leading to cervical cancer in women, penile cancer in men and oropharyngeal cancer in both sexes.

Most cases of HPV-related oral cancer are linked to oral sex, said Huang, noting that about 85 per cent of the cases in the CMAJ study were men.

HPV-related tumours respond better to treatment and have a higher survival rate than those linked to tobacco and alcohol use, the other major cause of oral cancer, she said, adding that early identification of a tumour’s cause is important to ensure appropriate and effective treatment.

While some centres in Canada routinely test oral tumours to determine their HPV status, such testing is not consistent across the country, the researchers say.

In the past, physicians generally tended to reserve tumour testing for cases most likely to be caused by HPV – among them younger males with no history of smoking and with light alcohol consumption – to prevent an unnecessary burden on pathology labs.

“Only as accumulating data have supported the clinical importance of HPV testing has routine testing been implemented in most (though not all) Canadian centres,” the researchers write.

The study showed that the proportion of new HPV-related oral cancers rose as those caused by non-HPV-related tumours fell between 2000 and 2012 – likely the result of steadily declining smoking rates.

Huang said males tend to have a weaker immune response to HPV than do females, which may in part explain the higher incidence of oral cancers linked to the virus in men.

HPV vaccines given to young people before they become sexually active can prevent infection – and the researchers say both boys and girls should be inoculated.

Currently, six provinces provide HPV immunization to Grade 6 boys as well as girls, with the other four provinces set to add males to vaccination programs this fall, said Huang.

“So vaccinating boys is very important because, if you look at Canadian Cancer Society statistics (for 2012), HPV- related oropharyngeal cancer in total numbers has already surpassed cervical cancers,” she said.
“The increase of HPV-related cancer is real, and it’s striking that there’s no sign of a slowdown.”

A novel vaccine therapy can generate immune responses in patients with head and neck squamous cell carcinoma (HNSCCa), according to researchers at the Abramson Cancer Center of the University of Pennsylvania. The treatment specifically targets human papillomavirus (HPV), which is frequently associated with HNSCCa, to trigger the immune response. Researchers will present the results of their pilot study during the 2017 American Society of Clinical Oncology Annual Meeting in Chicago (Abstract #6073).

HNSCCa is a cancer that develops in the mucous membranes of the mouth, and throat. While smoking and tobacco use are known causes, the number of cases related to HPV infection – a sexually transmitted infection that is so common, the Centers for Disease Control says almost all sexually active adults will contract it at some point in their lifetimes – is on the rise. The CDC now estimates 70 percent of all throat cancers in the United States are HPV-related. Sixty percent are caused by the subtype known as HPV 16/18.

“This is the subtype we target with this new therapy, and we’re the only site in the country to demonstrate immune activation with this DNA based immunotherapeutic vaccine for HPV 16/18 associated head and neck cancer,” said the study’s lead author Charu Aggarwal, MD, MPH, an assistant professor of Hematology Oncology in the Perelman School of Medicine at the University of Pennsylvania.

The vaccine is delivered as an injection of antigens – which leads the immune system to start producing antibodies and activate immune cells. At the time of injection, physicians use a special device to deliver a pulse of electricity to the area, which stimulates the muscles and speeds the intake of the antigens. Aggarwal noted that this study represents a multidisciplinary approach involving the lab and the clinic.

“This is truly bench-to-bedside and shows the value of translational medicine within an academic medical center,” Aggarwal said.

Penn researchers treated 22 patients with the vaccine. All of the patients had already received therapy that was intended to be curative – either surgery or chemotherapy and radiation. When doctors followed up an average of 16 months later, 18 of those patients showed elevated T cell activity that was specific to HPV 16/18. All of the patients in the study are still alive, and none reported any serious side effects.

“The data show the therapy is targeted and specific, but also safe and well-tolerated,” Aggarwal said.

Because of the positive activity, Aggarwal says the next step is to try this therapy in patients with metastatic disease. A multi-site trial will open soon that combines the vaccine with PD-L1 inhibitors, which target a protein that weakens the body’s immune response by suppressing T-cell production.